Present day PET/CT: a dual-imaging modality in oncology
Clinically, PET/CT has become an integral part of patient management in oncology, neurology and cardiology. By far, oncology accounts for most PET/CT applications.
Applications in oncology
Cancerous cells have higher metabolic rates. They use more glucose than normal cells. The most widely available PET/CT radiopharmaceutical today is an analogue of glucose labeled with 18F, fluoro-2-deoxy-D-glucose (18F-FDG) which has a half-life of 110 minutes. It was first used in neuro-oncology by a team led by Di Chiro in the 1980s1 and then in the detection of lung cancer in the 1990s. 18F-FDG is injected into the bloodstream, then transported into the interstitial space from where specific glucose transporters transport it into cells. Malignant transformation is associated with increasing energy demands and upregulation of these glucose transporters (especially GLUT-1). Like glucose, 18F-FDG is phosphorylated by hexokinase to 18F-FDG-6-phosphate. Unlike glucose though, 18F-FDG lacks a hydroxyl group on the 2-position and its metabolite 18F-FDG-6-phosphate cannot act as a substrate for glycolysis, hence the positron-emitting tracer is trapped in the cell without being further metabolized. Dephosphorylation is slow. Also unlike glucose, 18F-FDG is eliminated via the kidneys and very little is reabsorbed in the renal tubules, leaving low 18F-FDG levels in blood.
18F-FDG PET/CT has become an established technique for diagnosis, staging, detection of residual/recurrent cancer, and now also in planning therapy (Table 1). Numerous studies demonstrate how PET/CT is essential in staging and re-staging of the following cancers: breast, cervical, colorectal, oesophageal, head and neck, lymphoma, non-small cell lung, small cell lung, ovarian, thyroid, testicular and pancreatic carcinoma, melanoma, soft tissue sarcoma, and solitary pulmonary nodules. To illustrate further the clinical utility of 18FDG PET/CT and to emphasize the fact that many times this imaging technique cannot be replaced by any other modalities, some representative and common clinical situations are illustrated below:
A. In patients with ‘radiologically indeterminate’ pulmonary nodules, doctors either opt for a risky wait-and-see or an invasive biopsy which could be marred by complications, or false negatives, especially in hard-to-reach locations and in cases of inadequate tissue collection. PET/CT has a very high negative predicative value. When negative, a biopsy is avoided. PET/CT permits the differentiation of benign from malignant lesions, eg. of lesions seen on mammography.
B. PET/CT is more sensitive than CT in pre-operative staging of most carcinomas, eg. in esophageal carcinomas, up to one third of patients deemed operable by CT may have unsuspected metastases which may be identified by PET/CT, hence drastically altering management2.
C. A drawback of cross-sectional imaging techniques is their reliance on size criteria to define disease (eg. lymph nodes), with the consequent failure to detect disease in small lymph nodes (metastases from any primary cancer) and exclude disease in large but treated masses. 18F-FDG permits distinction of suspicious lymph nodes as malignant or disease-free, avoiding unnecessary biopsies or mediastinoscopies. PET/CT staging and restaging (assessment of therapy) of Hodgkin’s and non-Hodgkin’s lymphoma has practically replaced completely CT and gallium scintigraphy when available.
D. In some carcinomas it is possible to follow-up using tumour markers, as is in the case of colorectal (CEA), ovarian (CA125), breast (CA15.3) and pancreatic (CA19.9) carcinomas. Patients with rising tumour markers in follow-up often present with negative conventional morphological imaging. PET/CT allows the addition of early metabolic change data to the morphological images, determining the cause of tumour marker rise and permitting earlier therapeutic intervention.
E. Increased tumour uptake is a function of proliferative activity and is also related to viable tumour cell number. Hence, if 18F-FDG is related to tumour cell viability, then reduction in uptake (with effective chemotherapy) should reflect increased tumour cell killing rate. Clinical trials have demonstrated uptake of 18F-FDG as an early and sensitive pharmacodynamic marker of the anti-tumoral effect of chemotherapy, even as early as the first cycle of chemotherapy. An oncologist can now evaluate a therapy regime efficacy even after just one chemotherapy session using this imaging technique, and can also change the regime immediately, avoiding extra costs wasted in useless therapies and saving the patient from side-effects from a therapy which is not giving any benefits.
F. Post-radiotherapy PET/CT helps determine whether any residual viable tumour is still present. This is difficult to distinguish on CT because both scar tissue (radiotherapy changes) and disease can alter anatomy. When a patient presents with a tumour (as in lung carcinoma) with surrounding oedema, PET/CT permits the evaluation of the exact extent of the lesion, thus allowing better radiotherapy planning.
Dual-modality: PET and CT
Many might think that PET and CT were originally incorporated together as we know them today only to help doctors in accurately localizing the origin of tracer accumulation, giving patients a more definitive report. It was a physicist and an engineer (Townsend and Nutt) who implemented dual-modality. Attenuation is one of the major sources of artifact in PET, a process by which a beam of radiation is reduced in amplitude and intensity when passing through a material, in this case the radioactive signal emitted from a point source within the patient passing through the patient tissues. Attenuation is caused by a combination of absorption and scattering processes. The deeper within the body the source of radiation is, or the denser the tissues, the more the attenuation. To correct for attenuation, transmission (as opposed to emission) images derived from an external Germanium-68 or Gallium-68 positron-emitting source, or an external radioactive source which decays by emission of single events (Caesium-137), started being used. This required a blank scan and another transmission scan of the patient. These methods have been used successfully for many years, but were time-consuming and the radioactive source caused noisy transmission images propagated into the PET images. As stated above, a breakthrough occurred when high resolution, low noise CT transmission maps started being used. CT maps are obtained with X-rays of energy of 80 Kiloelectron Volts (KeV), while attenuation must be corrected in PET for photons of 511 KeV by attenuation correction algorithms. Besides a better quality attenuation
correction of PET images and significantly shorter scan times, the superimposition of CT to PET improved the interpretation of PET images because anatomic and structural characteristics of tissue were added to the physiologically mediated distribution of the tracer. PET/CT scanners can produce functional PET and anatomical CT data in one session, without moving the patient and with minimal delay between reconstruction and fusion of the two image data sets3. Hitting two birds with one stone!
1. De Chiro G, DeLaPaz R, Brooks R et al. Glucose utilisation of cerebral gliomas measured by 18F-fluorodeoxyglucose and PET. Neurology 1982; 32:1323.
2. Doung C, Demitriou H, Weih L et al. Eur J Nucl Med Mol Imaging 2006; 33:759-
3. Messa C, Bettinardi V, Picchio M et al. Q J Nucl Med Mol Imaging 2004; 48:66-75.